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New Mexico Cancer Care AllianceUniversity of New Mexico Cancer Center

Clinical Trial Template Instructions:

This template has been created to assist in the development of investigator-initiated interventional clinical trials. Please note that it has two parts. The objective of Part 1 is to provide a template and guidance for writing the protocol. The objective of Part 2 is to collect additional information required for review by the University of New Mexico Human Research Review Committee (HRRC)

Part 1 starts on the next page.Part 2 starts following Section 13 (Appendices) in this document

The sections/language in BLACK are standard language for the UNM Cancer Center and should be included in your study, unless they are not applicable.

The sections/language in BLUE are examples and instructions and should be modified according to your specific study design. PLEASE DELETE any sections that do not apply.

The local study number (identifier) in GREEN will be assigned by the Clinical Trials Office upon receipt of the final version of your protocol.

When the document is complete, all remaining sections in BLUE should either be omitted or modified to the specifications of your study and updated to BLACK type.

Version Date: XX/XX/XXXX

CONFIDENTIALThis material is the property of the New Mexico Cancer Care Alliance (NMCCA).

Do not disclose or use except as authorized in writing by the study sponsor (NMCCA).


PLEASE SPECIFY YOUR STUDY TYPE:

INTERVENTIONAL PROTOCOL(Treatment; Prevention; Supportive Care)

~ OR ~

OBSERVATIONAL PROTOCOL

PROTOCOL NUMBER= INST _____

(To Be Assigned by NMCCCA Clinical Trials Assistant)

COMPLETE PROTOCOL TITLE

Please include all of the following elements in the title as applicable:a) Type (e.g. interventional, observational); b) Phase (e.g., pilot/feasibility, phase I, phase II, etc.), c) D esign (e.g., randomized, double blind, placebo controlled, etc.),d) Breadth (if the study is multi-center (outside UNMCC and NMCC Alliance) OR single center

(includes UNMCC Consortium partners and/or NMCC Alliance Sites); e) the Investigational agent, and f) Target disease(s) and stage (e.g. advanced, relapsed/refractory, Her2 negative, etc.)

Principal Investigator: NameInstitutionAddress(Phone) (Fax)E-mail

Sub-Investigator(s): For UNM sub-Is include:NameDepartment/Division

For off-site sub-Is include:NameInstitutionAddress(Phone) (Fax)E-mail

Biostatistician: NameVersion Date: XX/XX/XXXX




InstitutionAddress(Phone) (Fax)E-mail

Study Agent: Generic study drug name or number, followed by marketed name (ifapplicable)

Study Sponsor: New Mexico Cancer Care Alliance (Replace as needed; e.g., CTEP)PO Box 4428Albuquerque, New Mexico

IND Number: Insert IND Number, if applicable. (Delete if N/A.)

IND Holder Name: New Mexico Cancer Care Alliance. (Replace, or Delete if N/A.)

Funding Source(s): List support (funding or investigational agent from Pharmaceutical Company(ies), Federal Grant, UNM Cancer Center, or other source. Provide grant number, if applicable.)

Initial version: DRAFTS: (0.1, 0.2, 0.3, etc.) See Version Management Guidelines

FINAL VERSIONS: [Version 1.0] and [Date] (This should be the final version that was sent to Clinical Working Group and Protocol Review & Monitoring Committee)

Amended: [Version nnn] and [Date of revision] – (Maintain running list of all amendments here)





Study Number: INST ______________

SIGNATURE PAGE

The signature below constitutes the approval of this protocol and all attachments as necessary. It provides the necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal regulations and ICH guidelines.

Principal Investigator (PI) Name (please type):

PI Signature: _____________________________

Date: ____________________




Study Number________________________________________________________________________

TABLE OF CONTENTS

LIST OF ABBREVIATIONS .................................................................................. 1

STUDY SCHEMA .................................................................................................. 3

STUDY SUMMARY ............................................................................................... 3

1.0 BACKGROUND AND RATIONALE ..................................................... 6

1.1 Disease Background.......................................................................................................6

1.2 Study Agent(s) Background and Associated Known Toxicities.......................................6

1.3 Other Agents................................................................................................................... 6

1.4 Rationale........................................................................................................................ 6

1.5 Correlative Studies.........................................................................................................6

2.0 STUDY OBJECTIVES .......................................................................... 6

2.1 Primary Objectives..........................................................................................................7

2.2 Secondary Objectives.....................................................................................................7

2.3 Exploratory Objectives....................................................................................................7

2.4 Endpoints........................................................................................................................ 7

3.0 PATIENT ELIGIBILITY ......................................................................... 7

3.1 Inclusion Criteria.............................................................................................................8

3.2 Exclusion Criteria............................................................................................................8

4.0 TREATMENT PLAN ............................................................................. 9

4.1 Treatment Dosage and Administration...........................................................................9

4.2 Toxicities and Dosing Delays/Dose Modifications.........................................................10

4.3 Concomitant Medications/Treatments..........................................................................13

4.4 Other Modalities or Procedures....................................................................................13

4.5 Duration of Therapy......................................................................................................13

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Study Number________________________________________________________________________

4.6 Duration of Follow Up...................................................................................................13

4.7 Removal of Patients from Protocol Therapy.................................................................13

4.8 Patient Replacement....................................................................................................14

5.0 STUDY PROCEDURES ...................................................................... 14

5.1 Screening/Baseline Procedures....................................................................................14

5.2 Procedures During Treatment.......................................................................................15

5.3 Follow-up Procedures...................................................................................................15

5.4 TIME AND EVENTS TABLE (STUDY CALENDAR).....................................................15

5.5 Removal of Subjects from Study...................................................................................16

6.0 MEASUREMENT OF EFFECT (OUTCOME MEASURES) ................ 16

6.1 Antitumor Effect- Solid Tumors.....................................................................................17

6.2 Antitumor Effect- Hematologic Tumors.........................................................................21

6.3 Safety/tolerability..........................................................................................................21

7.0 ADVERSE EVENTS ........................................................................... 21

7.1 Experimental Therapy...................................................................................................21

7.2 Adverse Event Monitoring.............................................................................................21

7.3 Definitions.....................................................................................................................22

7.4 Steps to Determine If an Adverse Event Requires Expedited Reporting......................23

7.5 Reporting Requirements for Adverse Events................................................................23

7.6 Unblinding Procedures.................................................................................................26

7.7 Stopping Rules.............................................................................................................26

8.0 DRUG OR OTHER AGENT INFORMATION ...................................... 26

8.1 Agent XXX....................................................................................................................26

9.0 CORRELATIVES/SPECIAL STUDIES (As Applicable) .................... 27

9.1 Sample Collection Guidelines.......................................................................................27

9.2 Assay Methodology (with references)...........................................................................28

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Study Number________________________________________________________________________

9.3 Specimen Banking........................................................................................................28

10.0 STATISTICAL CONSIDERATIONS ................................................... 28

10.1 Study Design/Study Endpoints.....................................................................................29

10.2 Sample Size and Accrual..............................................................................................29

10.3 Data Analyses Plans.....................................................................................................29

11.0 STUDY MANAGEMENT ..................................................................... 29

11.1 Conflict of Interest.........................................................................................................29

11.2 Institutional Review Board (IRB) Approval and Consent...............................................29

11.3 Required Documentation..............................................................................................30

11.4 Registration Procedures...............................................................................................30

11.5 Adherence to the Protocol............................................................................................31

11.6 Amendments to the Protocol.........................................................................................31

11.7 Record Retention..........................................................................................................32

11.8 Obligations of Investigators...........................................................................................32

12.0 REFERENCES .................................................................................... 33

13.0 APPENDICES ..................................................................................... 33

Appendix A: Data Management and Monitoring/Auditing……..................………………………33

Appendix B: Electronic Case Report Forms Required for this Study…… ………………………33

Appendix C: [Other Appendices as applicable]……..................................………………………33

14.0 ADDITIONAL INFORMATION FOR HRRC REVIEW ......................... 33

14.1 Regulatory Framework:................................................................................................34

14.2 Study Timelines............................................................................................................34

14.3 Research Setting..........................................................................................................34

14.4 Resources Available.....................................................................................................35

14.5 Prior Approvals.............................................................................................................35

14.6 Multi-site Research.......................................................................................................35

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Study Number________________________________________________________________________

14.7 Study Procedures.........................................................................................................36

14.8 Data Management/Confidentiality.................................................................................36

14.9 Data and Specimen Banking........................................................................................36

14.10 Risks to Subjects..........................................................................................................37

14.11 Prior Approvals.............................................................................................................37

14.12 Recruitment Methods....................................................................................................37

14.13 Provisions to Protect the Privacy Interests of Subjects.................................................38

14.14 Economic Burden to Subjects.......................................................................................38

14.15 Compensation...............................................................................................................39

14.16 Compensation for Research-Related Injury..................................................................39

14.17 Consent Process..........................................................................................................39

14.18 Documentation of Consent...........................................................................................41

14.19 Study Test Results/Incidental Findings.........................................................................41

14.20 Sharing Study Progress or Results with Subjects.........................................................42

14.21 Inclusion of Vulnerable Populations..............................................................................42

14.22 Community Based Participatory Research...................................................................42

14.23 Research Involving Native American Indian/Native Populations...................................42

14.24 Transnational Research................................................................................................43

14.25 Drugs or Devices..........................................................................................................43

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Study Number________________________________________________________________________

LIST OF ABBREVIATIONS (ADD TERMINOLOGY SPECIFIC TO YOUR STUDY)

AE Adverse EventALT Alanine AminotransferaseALC Absolute Lymphocyte CountAST Aspartate AminotransferaseBUN Blood Urea NitrogenCBC Complete Blood CountCMP Comprehensive Metabolic PanelCR Complete ResponseCRF Case Report FormCT Computed TomographyCTCAE Common Terminology Criteria for Adverse EventsDLT Dose Limiting ToxicityDSMB Data and Safety Monitoring BoardDSMP Data and Safety Monitoring PlanH&P History & Physical ExamHRPP Human Research Protections ProgramICF Informed Consent FormIND Investigational New DrugIV (or iv) Intravenous(ly)

iwCLL 2008International Workshop on Chronic Lymphocytic Leukemia 2008 (Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia)

LTFU Long Term Follow UpMRI Magnetic Resonance ImagingMTD Maximum Tolerated DoseNCI National Cancer InstituteNMCCA New Mexico Cancer Care AllianceORR Overall Response RateOS Overall SurvivalPBMCs Peripheral Blood Mononuclear CellsPD Progressive DiseasePET Positron Emission TomographyPFS Progression Free Survivalp.o. per os/by mouth/orallyPR Partial ResponseRECIST Response Evaluation Criteria in Solid Tumors SAE Serious Adverse EventSD Stable DiseaseSGOT Serum Glutamic Oxaloacetic TransaminaseSPGT Serum Glutamic Pyruvic TransaminaseUNMCC University of New Mexico Cancer CenterUPIRSO Unexpected Problems Involving Risks to Subjects and Others

Page 1 of 53 Version Date: XX/XX/XXXX

Study Number________________________________________________________________________

Velos Velos, Inc. eResearch Clinical Trials Management System (CTMS)WBC White Blood Cells


Study Number________________________________________________________________________

STUDY SCHEMAThe schema should represent your study design, along with corresponding descriptive text, as applicable. For example:

STUDY SUMMARY

IMPORTANT: ClinicalTrials.gov and NCI CTRP Data Element Definitions:

Study Type ‐ Designation of study as ‘Observational’ or ‘Interventional’ is consistent with other information in the record and with the ClinicalTrials.gov Protocol Data Element Definitions:

InterventionalStudies in human beings in which individuals are assigned by an investigator based on a protocol to receive specific interventions. Subjects may receive diagnostic, therapeutic or other types of interventions. The assignment of the intervention may or may not be random. The individuals are then followed and biomedical and/or health outcomes are assessed.

Hint: Randomized studies are interventional. Studies with investigational drugs or devices are likely to be interventional.

ObservationalStudies in human beings in which biomedical and/or health outcomes are assessed in pre‐defined groups of individuals. Subjects in the study may receive diagnostic, therapeutic, or other interventions, but the investigator does not assign specific interventions to the subjects of the study.

Full Title Full title of protocol

Short Title Shortened title (match this to title used for ClinicalTrials.gov reporting)

Study Sponsor(s) and Sponsor study reference numbers, if any

Protocol NumberThe local protocol number used to identify this study (INST xxxx), to be assigned by the New Mexico Cancer Care Alliance Clinical Trials Assistant

Phase Clinical study phase (e.g., Pilot/Feasibility; Phase 1, 2, or 3)


Study Number________________________________________________________________________

Study Type (please see above distinctions)

Therapeutic intervention; Prevention intervention; Supportive Care; Observational; Diagnostic, etc.

Study Design/MethodologyDesign attributes such as: single blinded, double blind or open label; randomized, non-randomized, placebo or active placebo-controlled; cross-over design, etc.

Study DurationEstimated duration for the main protocol (e.g., from start of screening to last subject processed and finishing the study including long term follow up) NOTE: Long Term Follow Up must have clear maximum time period

Study Center(s)Single-center or multi-center; if multi-center, note number of projected centers to be involved (NOTE: UNMCC and its consortium partners, including NMCC Alliance sites, constitute a single Center)

Objectives

Brief statement of primary study objective (only one) and secondary objective(s)PLEASE INCLUDE: A statement defining the specific time at which these objectives will be measured. For example, “Progression free survival will be evaluated at 5 years after treatment has ended.” Or – “Overall response rate will be evaluated up to 6 months after treatment has ended.” For registration and reporting purposes, clinicaltrials.gov requires this specific information.

Number of Subjects (National or International Target)

Maximum number of subjects projected for the entire study (at all participating study sites)

Diagnosis and Main Inclusion Criteria

Note the main clinical disease state under study and the key inclusion criteria (i.e., not the entire eligibility inclusion/exclusion criteria listing that will appear later in the protocol, rather only the primary inclusion criteria)

Study Product(s), Dose, Route, Regimen

Study drug, agent or vaccine name(s) (generic name, also marketed name if name-brand used in the study) and/or description of non-drug therapy (i.e., radiation, surgery, etc.); include dose(s), route(s) and regimen(s). Include IND number if applicable.

Note: Regarding drug names, please use the generic name of a drug, if available. If more than one drug name is being used for the same drug (e.g., a generic name and a brand name), clearly indicate that one drug is the same as the other.

The preferred format is to include one drug name in parentheses next to the other drug name, for example: (Abiraterone acetate) (Zytiga®)

Duration of administration Total duration of drug or other agent administration (including any open-label lead-in, if applicable)


Study Number________________________________________________________________________

Reference therapy

Note clearly if there is a standard reference therapy (standard of care for specific disease, stage) against which the study product is being compared, or if the reference is a placebo.

Clearly identify the number of study arms. Include a title or reference (“Arm A” and “Arm B”) for each arm.

Note: “Active Comparator” or “Placebo Comparator” cannot be the only Arm Type for a “Single Group Assignment” study design. The presence of a “Comparator” suggests that there is more than one Arm (to what the "Active Comparator" is being compared). Registration at ClinicalTrials.gov will be rejected if incorrectly stated.

If an intervention is assigned to an Arm, “No Intervention” is not an appropriate Arm Type

Statistical Methodology

A brief description of the main elements of the statistical methodology to be used in the study, including UNITS of measure for EACH objective and methodology applicable to EACH evaluation. This must be included in the study record for applicable trials registered at ClinicalTrials.gov for results reporting.


Study Number________________________________________________________________________

1.0 BACKGROUND AND RATIONALE

1.1 Disease BackgroundPlease provide disease background information relevant to your study, with appropriate references. Questions to be addressed may include the current standard of care (SOC) and any relevant treatment issues or controversies. Please justify clearly why an investigational therapy or approach is warranted.

1.2 Study Agent(s) Background and Associated Known ToxicitiesPlease provide relevant background information about the study agent(s) that you are planning to use in the study, with their known toxicities. The following briefly explains what is required in this section:

A summary of findings from non-clinical in vitro/in vivo studies that have potential clinical significance including information on mechanism of action, pharmacokinetics and known safety issues. This is particularly important for investigational agents, and may not be necessary for commercially available drugs if approved for use in your specific patient population.

A summary from relevant clinical studies, with focus on those that provide background for your study. Please include important safety information, the rationale for the starting dose(s), information on clinical pharmacokinetics (PK), and major route(s) of elimination. If available, please include information on the metabolism of the agent(s) in humans and address any known or theoretical potential for drug interactions.

1.3 Other AgentsThis section may be required if your study focuses on either an investigational agent in combination with commercially available products, or if your primary objective focuses on only one of several commercial agents included in the study. If needed, please provide background information on other agent(s) and/or treatments in this study that are not described in section 1.2 including rationale for including them in this study, their mechanism(s) of action, information to address safety issues and the rationale for the proposed starting dose scheme, if applicable. For commercially available agents, detailed information on adverse events and potential risks should be deferred until Section 8.0 (Drug/Agent Information).

1.4 RationaleDiscuss reasoning behind conducting the study and your study design. Include justification of your individual study endpoints. This section should clearly link the disease background with the study agent(s) under evaluation. Include study population rationale, particularly if focusing on a subset within the disease population (e.g., relapsed or elderly patients).

1.5 Correlative StudiesIf applicable, please provide the background information on the planned correlative study(ies) including the biological rationale and hypothesis.

2.0 STUDY OBJECTIVES


Study Number________________________________________________________________________

Please include a detailed description of Primary and Secondary objectives of the study. Each objective should receive a separate number, e.g., 2.1.1, 2.1.2. As an example, the following guidelines can be used to describe these objectives:

Statement of purpose: e.g., to describe, to measure, to compare, to estimateGeneral purpose: e.g., efficacy, safety, immunogenicity, pharmacokineticsSpecific purpose: e.g., dose-response, potential superiority to placebo or standard of care

2.1 Primary ObjectivesNote: ClinicalTrials.gov strongly encourages having only 1 primary objective and endpoint.

A typical primary objective for a phase I trial is:“To determine the dose-limiting toxicity (DLT) and maximally tolerated dose for (insert Study Agent) when administered (insert schedule and list other drugs given in combination with Study Agent, if applicable) in patients with (insert tumor type, sub-type, etc.).”

Each objective (whether primary, secondary or exploratory) must be assigned a separate number and must have a corresponding endpoint described in section 2.4.

2.2 Secondary Objectives Typical secondary objectives for a phase I trial include:

2.2.1 “To describe the adverse events associated with (insert Study Agent) when administered (insert schedule and list other drugs given in combination with Study Agent, if applicable) in patients with (insert tumor type, sub-type, etc.)”

2.2.2 “To describe the pharmacokinetics associated with (insert Study Agent) when administered (insert schedule and list other drugs given in combination with Study Agent, if applicable) in patients with (insert tumor type, sub-type, etc.)”

2.2.3 ”In patients with measurable disease, to describe any preliminary evidence of anti-tumor activity by assessment of objective response as determined by (insert response criteria) in patients with (insert tumor type, sub-type, etc.)”

2.3 Exploratory ObjectivesIf applicable, please include specific objective(s) for your correlative studies with reference to specific tissue repositories or controls involved.

2.4 EndpointsSpecify which primary endpoint(s) will be used to answer your primary objective. Specify which secondary endpoints will be used to address your secondary objectives. Endpoints should also be clearly described for exploratory objectives. A typical endpoint for the primary objective example in 2.1 would be “DLT will be defined based on the rate of drug-related grade 3-5 adverse events experienced within the first 8 weeks (2 cycles) of study treatment. These will be assessed via NCI’s CTCAE v4.0 toxicity criteria. The MTD will be defined, etc.”

3.0 PATIENT ELIGIBILITYEligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study treatment may not begin until a subject is registered.


Study Number________________________________________________________________________

3.1 Inclusion CriteriaEach criterion should include its own number, e.g., 3.1.1, 3.1.2, etc.

For example:3.1.1 Diagnosis/disease status

3.1.2 Allowable type and amount of prior therapy

3.1.3 Age ≥ 18 years.

3.1.4 ECOG Performance status

3.1.5 Adequate organ and marrow function as defined below:- leukocytes ≥ 3,000/mcL- absolute neutrophil count ≥ 1,500/mcL- platelets ≥ 100,000/mcl- total bilirubin within normal institutional limits- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal- creatinine within normal institutional limits

3.1.6 Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

3.1.6.1 A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive

months (i.e., has had menses at any time in the preceding 12 consecutive months).

3.1.7 Other study-specific criteria

3.1.8 Ability to understand and the willingness to sign a written informed consent document.

3.2 Exclusion Criteria

For example:3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks prior to

entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

3.2.2 Patients may not be receiving any other investigational agents. If a “washout” period is required, describe specific time frames.

3.2.3 Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.


Study Number________________________________________________________________________

3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic composition to Agent(s) or other agents used in study.

3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.6 Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

4.0 TREATMENT PLAN

4.1 Treatment Dosage and Administration

4.1.1 For complex studies (e.g., multiple treatment phases) please first provide a summary of the entire treatment plan. This should be a few sentences, which provide a “snapshot” of the treatment plan. Describe specific details below.

4.1.2 Please provide a full description of the treatment plan and how it will be administered (inpatient/outpatient basis). Include a complete description of any definite required or recommended/suggested supportive care medications.

See the example below for how the planned treatment regimen may be presented. Please provide separate regimen descriptions for different treatment groups of patients as necessary. IMPORTANT: List the agents in the correct sequence in which they will be administered.

If pre-medications are to be used, you may list “Physician Discretion” as necessary.

REGIMEN DESCRIPTION

AgentPremedications;Precautions Dose Route Schedule

Cycle Length

Agent X Pre-medicate with DRUG for 3 days prior to Agent X.

300 mg/m2 in 500 cc NS

IV over 2 hours before Agent Y

Days 1-3, week 1

4 weeks (28 days)

Agent Y Avoid exposure to cold (food, liquids, air) for 24 hrs after each dose.

150 mg/m2 in 250 cc D5W

IV 1 hr after completion of Agent Y; separate IV line required

Days 1-3, week 1

Agent Z Take with food. 50 mg tablet p.o. in the a.m. Daily, wks 1 & 2

For phase I dose-escalation studies: Please state the starting dose of the study agent/drug and describe the dose escalation scheme and treatment regimen. Use exact dose rather than percentages. Please describe the number of patients to be treated at each level and how a decision about dose escalation or expansion of cohort sizes will be made. If there are multiple agents being used in the study, include dose escalation for each agent. Please note that escalation of only one drug at each dose level is recommended.


Study Number________________________________________________________________________

Please use the following table as a guideline to describe the dose escalation scheme:

Dose-Escalation Schedule

Dose Level Dose of the Study Agent(s)*Minimum

Number of Patients

Level -1 3Level 1 3Level 2 3Level 3 3Level 4 3*Doses must be stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage

Dose-Limiting Toxicity (DLT) and Maximally Tolerated Dose (MTD) : Please provide explicit definition of type(s), grade(s) and duration of adverse event (s) that will be considered dose-limiting, or provide definitions of other endpoints that will be used to determine dose escalations if applicable. Please note any definite exclusions from the DLT definition (e.g., if a rule states any grade 3/4 hematologic toxicity is a DLT but this EXCLUDES lymphopenia of any grade.)

Please give the specific timeframe for DLT evaluation (e.g., after 1st cycle of therapy, any time during treatment, etc.). Please also describe how you will determine the MTD, and if applicable, the recommended phase 2 dose (these will likely be one and the same). Ensure this section is consistent with the statistical section of your protocol.

Please state any special precautions or warnings relevant for agent administration (e.g., incompatibility of agent with commonly used intravenous solutions, necessity of administering agent with food, pre-medications, hydration, whether any monitoring of vital signs during or shortly after treatment is required, etc.). If treatment will be self-administered (i.e. oral drug or self-injection), please reference any subject tools that will be implemented (study medication diary, subcutaneous injection instruction sheets, etc); please also state how missed (or vomited) doses will be handled.

4.2 Toxicities and Dosing Delays/Dose ModificationsAny patient who receives treatment on this protocol will be evaluable for toxicity. Each patient will be assessed for the development of toxicity according to the Study Schedule (Time and Events) table (Insert Appropriate Section Number). Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Dose adjustments should be made according to the system showing the greatest degree of toxicity.

Treatment plans should explicitly identify when treatment (typically dosage) modifications are appropriate. Treatment modifications/dosing delays and the factors predicating treatment modification should be explicit and clear. For phase I studies, there must be consistency between toxicities which mandate dose reductions, and those events which are considered a DLT.

If dose modifications or treatment delays are anticipated, please provide a dose de-escalation schema.


Study Number________________________________________________________________________

If there are multiple agents being used in the study, provide a detailed description of toxicity grades and method of dose modification for each agent separately. In the event that more than one study agent could be responsible for a given toxicity, please address in what order each agent should be modified/delayed and provide justification (if available). Reference the specific section in the protocol that contains more detailed information on the potential adverse events and risks associated with each agent (either in Section 1.2,1.3 or Section 8.0). All treatment modifications should be expressed as a specific dose or amount rather than as a percentage of the starting or previous dose.

Please also identify how many missed days of treatment or missed cycles will warrant removal of the patient from the study. If patients may remain on study after missed days or cycles, please specify when treatment under study may resume.

Note: please consider separating dose modification criteria/schema for hematological versus non-hematological criteria. For hematological toxicity, please address guidance on use of specific growth factor(s). If applicable, include a summary in table format. The following tables are provided as examples and should be modified as appropriate:

Toxicity Table Example 1: Hematological Toxicities

Hematological Toxicity Dose Reductions for Agent A

ANC1 Platelets Action≥ 1,500/L 100,000/ L None.

1000-1499/L 75,000-99,000/ L -1st Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.

-2nd Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.

-3rd Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.

-4th Occurrence: Discontinue protocol therapy.

500-999/L 50,000-74,000/ L -1st Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.

-2nd Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at TBD dose.

-3rd Occurrence: Discontinue protocol therapy.

<500/L <50,000/ L -1st Occurrence: Hold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. Restart next treatment at TBD dose.

-2nd Occurrence: Discontinue protocol therapy.


Study Number________________________________________________________________________

1Note: G-CSF (Filgrastim) may be added for low ANC on day of treatment BEFORE a dose reduction is instituted at treating physician’s discretions. Neulasta® is NOT allowed.

Toxicity Table Example 2a: Non-hematological Toxicities: Modifications for several agents at once may be presented. Any exceptions should be further explained in the text of the protocol.

Non-hematological Toxicity Dose ReductionsNCI CTC Grade Agent A Agent B Agent C

0-2 No change from original starting dose (Note any exceptions here and address in text)

No change from original starting dose (Note any exceptions here and address in text)

No change from original starting dose (Note any exceptions here and address in text)

3 Hold until resolved to < Grade 2, then reduce to TBD dose

Hold until resolved to < Grade 2, then reduce to TBD dose


Second episode of grade 3 or 4 toxicity




Third episode of grade 3 or 4 toxicity

Remove subject from trial



Toxicity Table Example 2b: Non-hematological Toxicities: Each agent to be modified may be described in an individual table.

AGENT 1: Example of non-hematological Toxicity Dose Reductions

Event ActionName of ToxicityGrade 1-2 NoneGrade 3 Insert dose modification, may want to specify if

first allow attempt at control, e.g., with anti-emetics prior to dose modification

Grade 4Name of Separate ToxicityGrade 1-2Grade 3

AGENT 2: Example of non-hematological Toxicity Dose Reductions

Event ActionName of ToxicityGrade 1-2 NoneGrade 3 Insert dose modification, may want to specify if

first allow attempt at control, e.g., with anti-emetics prior to dose modification

Grade 4Name of Separate ToxicityGrade 1-2Grade 3


Study Number________________________________________________________________________

4.3 Concomitant Medications/TreatmentsPlease list all relevant concomitant drugs and/or treatments that are prohibited. This section should be consistent with the medications restrictions in the inclusion/exclusion criteria.

If any medications may be used, but only with caution, please address that in this section.

4.4 Other Modalities or ProceduresIf applicable, please provide a detailed description of any other modalities (e.g., surgery, radiotherapy) or procedures (e.g., hematopoietic stem cell transplantation) used in the protocol treatment. Please clearly distinguish between those modalities that comprise standard of care versus those under investigation in your protocol. This is very important for ethical (IRB) review and billing purposes.

4.5 Duration of TherapyThis section should unambiguously define the “end of protocol therapy.” For example: “In the absence of treatment delays due to adverse events, treatment may continue for TBD or until:

Disease progression as determined by XXXXX (specific methodology) Inter-current illness that prevents further administration of treatment Unacceptable adverse event(s) as outlined in Table(s) XXXX Patient decides to withdraw from the study, OR General or specific changes in the patient’s condition render the patient

unacceptable for further treatment in the judgment of the investigator”.

4.6 Duration of Follow UpInclude information regarding follow-up, for example, “Patients will be followed for TBD after removal from treatment or until death, whichever occurs first. Patients removed from treatment for unacceptable adverse events will be followed until resolution or stabilization of the adverse event”.

Hint: for Phase I studies, subjects are usually considered “off study" at 30 days from last treatment. Follow-up in Phase II studies may vary (e.g., 2 to 5 or even 10 years or more) depending on whether patients are followed for a survival endpoint. Please consider this carefully, as following patients until death may require considerable resources, may not be necessary, and may delay publication of results. Please also state the nature and frequency of follow-up (e.g., clinical visits every 3 months, by phone call every 6 months, etc.).

PLEASE INCLUDE specific Follow Up items individually in the Time and Events table.

NOTE: For mandatory federal website reporting, Follow Up period must be given a maximum period in months or years. Please do not indicate “until last patient death,” as this will not be accepted by www.ClinicalTrials.gov.

4.7 Removal of Patients from Protocol TherapyPatients will be removed from therapy when any of the criteria listed in Section 5.5 apply. The Principal Investigator will be notified, and the reason for removal from therapy will be documented, including the date the patient was removed in a study Case Report Form.

NOTE: the patient should continue to be followed per protocol, as the discretion of the Principal Investigator or treating physician. The patient will be considered as an ongoing study participant until deemed off study by the Investigator, or withdraws consent for remaining protocol-specific follow up.


http://www.ClinicalTrials.gov/

Study Number________________________________________________________________________

4.8 Patient ReplacementPlease include guidelines describing when and how an enrolled patient may be replaced in the study. For example, “Three patients within a dose level must be observed for one cycle (28 days) before accrual to the next higher dose level may begin. If a patient is withdrawn from the study prior to completing 22 days of therapy without experiencing a DLT prior to withdrawal, an additional patient may be added to that dose level. Patients missing 7 or more doses due to toxicity will not be replaced since these patients will be considered to have experienced a dose limiting toxicity.”

5.0 STUDY PROCEDURES

5.1 Screening/Baseline ProceduresAssessments performed exclusively to determine eligibility for this study will be done only after obtaining written informed consent. Assessments performed for clinical indications (i.e., not exclusively to determine study eligibility) may be used for baseline values even if the assessments were done before informed consent was obtained.

All screening procedures must be performed within # days, weeks, or months prior to registration unless stated otherwise. Examples of screening procedures to include in the TIME AND EVENTS TABLE include:

5.1.1 Informed Consent – process including ICF completion

5.1.2 Medical historyComplete medical and surgical history, history of infections

5.1.3 DemographicsAge, gender, race, ethnicity

5.1.4 Review subject eligibility criteria

5.1.5 Review previous and concomitant medications

5.1.6 Physical exam including vital signs, height and weightVital signs (temperature, pulse, respirations, blood pressure), height, weight

5.1.7 Performance statusPerformance status evaluated prior to study entry according to Appendix #/letter.

5.1.8 Adverse event assessmentBaseline adverse events will be assessed. See section 6 for Adverse Event monitoring and reporting.

5.1.9 Hematology

5.1.10 Blood draw for correlative studiesSee Section 9.0 for details. List specific types of blood draw tubes to be used to ensure proper collection and processing of blood specimens.

5.1.11 Serum chemistriesComprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin.


Study Number________________________________________________________________________

5.1.12 Pregnancy test (for females of child bearing potential)See section 3.1.6.1 for definition.

5.1.13 Tumor assessmentTo be performed…

5.1.14 Other Describe…

5.2 Procedures During TreatmentTreatment may be broken down by cycle(s) or phase(s) – whatever makes the most sense given the overall plan. Examples of treatment phases might include neoadjuvant, adjuvant, initial, maintenance, etc.

5.2.1 Prior to Each Treatment Cycle Physical exam, vital signs Hematology Serum chemistries

5.2.2 Day 1 Procedure

5.2.3 30 days after treatment termination Physical exam, vital signs Hematology Serum chemistries

5.3 Follow-up ProceduresPatients will be followed every <time frame> after completion of (or early withdrawal from) study treatment until when. (MAXIMUM time must be expressed in months or years)

Procedure

5.4 TIME AND EVENTS TABLE (STUDY CALENDAR)Please see the example below; list the specific day or days if appropriate, e.g., Day 1, Cycle 1 or Days 1, 7… etc.). Please ensure table reconciles with all study objectives, eligibility criteria, and assessments following in sections 5.1-5.3.*

SAMPLE Pre-study Week 1 or Day/Days

Weekly or Day/Days

q 6 Weeks

Off Treatment

Follow-up

AssessmentInformed Consent

X

History and PE X X X XPerformance Status

X X X X

Toxicity (include DLT) Evaluations

X X X

Tumor Measurements

X X

Chest x-ray X X XCBC X X X X X


Study Number________________________________________________________________________

Other required labsInclude correlative Procedures (if applicable)

X X

*Include any necessary notes detailing specifics of procedures outlined in table.

5.5 Removal of Subjects from StudyPatients can be taken off the study treatment and/or study at any time at their own request, or they may be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) for discontinuation will be documented and may include:

5.5.1 Patient voluntarily withdraws from treatment (follow-up permitted);

5.5.2 Patient withdraws consent (termination of treatment and follow-up);

5.5.3 Patient is unable to comply with protocol requirements;

5.5.4 Patient demonstrates disease progression (unless continued treatment with study drug is deemed appropriate at the discretion of the investigator);

5.5.5 Patient experiences toxicity that makes continuation in the protocol unsafe;

5.5.6 Treating physician judges continuation on the study would not be in the patient’s best interest;

5.5.7 Patient becomes pregnant (pregnancy to be reported along same timelines as a serious adverse event);

5.5.8 Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma of the skin) that requires treatment, which would interfere with this study;

5.5.9 Lost to follow-up. Example language: If a research subject cannot be located to document survival after a period of 2 years, the subject may be considered “lost to follow-up.” All attempts to contact the subject during the two years must be documented and approved by the Data Monitoring Committee.

6.0 Measurement of Effect (OUTCOME MEASURES)Use appropriate section below (solid vs. liquid tumors).

IMPORTANT: ClinicalTrials.gov requirements state that:

The Outcome Measure information must include the name of the specific measure (e.g., Systolic Blood Pressure) and a description of the metric that will be used to characterize the measure (e.g., Change in Systolic Blood Pressure).

o Hint: “Bioequivalence,” “pharmacokinetics,” and “pharmacodynamics” alone are not acceptable as specific descriptions of an Outcome Measure because they do not specify by which particular measures will be assessed. Examples of acceptable Outcome Measure Titles to assess these parameters include:

• “Area under the plasma concentration versus time curve (AUC) of ‘drug x’”• “Peak Plasma Concentration (Cmax) of ‘drug x’”


Study Number________________________________________________________________________

o Hint: “Safety,” “tolerability,” and “feasibility” are not specific measures. Similarly, “Adverse events” by itself is not sufficient. “Number of participants with adverse events > grade 2” is specific.

The Outcome Measure information describes only WHAT will be measured, not why it is measured.

o Hint: Generally, verbs should not be included in the Outcome Measure Title.

Outcome Measure Time Frames

Per CT.gov requirements, each Outcome Measure must include a time point at which the outcome is assessed for the specific metric used. Most outcome measures will have one time point.

If multiple outcomes are based on the same underlying measure (e.g., Outcome Measure Title “Change from Baseline in Hamilton Depression Rating Scale”) but are assessed at different time points (e.g., “8 weeks and 12 weeks”), then each unique combination of measurement and Time Frame is entered as a separate Outcome Measure (e.g., “Change from Baseline in Hamilton Depression Rating Scale at 8 weeks” and “Change from Baseline in Hamilton Depression Rating Scale at 12 weeks”).

o “Change” Outcome Measures – Generally two time points (e.g., “baseline and 8 weeks”) are entered to indicate the time period over which the change occurred

o Time ‐ to ‐ Event Outcome Measures – This measure describes plans to assess the time to occurrence of an “event” (e.g., “death”). The Time Frame should, at a minimum, include the estimated period of time over which the event will be assessed (e.g., “up to 100 weeks”). The Time Frame may also include information on how the event will be determined and over what estimated period of time (e.g., “From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months”).

o Pharmacokinetic Outcome Measures (e.g., Cmax, AUC) – These assessments rely on multiple measurements over time and the Time Frame may include multiple time points describing the interval at which data are collected (e.g., “0, 1, 2, 3, 4, 6, 8, 12 , 24, 48, 72, 96 hours post‐dose”).

o Hint: “At follow‐up” or “end of study” is usually not an adequate Time Frame. At a minimum, the Time Frame should include the maximum length of follow‐up that is currently planned (e.g., “up to 3 years”).

Exceptions are possible, for example, in measures that are assessed at the particular time the intervention is administered (e.g., “at time of surgery”).

6.1 Antitumor Effect- Solid Tumors

Define/describe the criteria to be utilized (iwCLL, RANO, RECIST, other) and, if necessary, please provide your justification and references.

If using RECIST, state:

Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST)


Study Number________________________________________________________________________

Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria.

6.1.1 DefinitionsEvaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with study drug.

Evaluable for objective response. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)

If using RECIST, state:

6.1.2 Disease ParametersMeasurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements will be recorded in millimeters (or decimal fractions of centimeters) in this study.

Note: Previously irradiated lesions are non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy.

Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), will be considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are examples of non-measurable disease.

Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 lesions in total, representative of all involved organs, will be identified as target lesions and recorded and measured at baseline. Target lesions will be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.

Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 6 target lesions will be identified as non-target lesions and will also be recorded at baseline. Measurements of these lesions are not required for study analyses, but the presence or absence of each will be noted throughout follow-up.

6.1.3 Methods for Evaluation of Measurable DiseaseAll measurements will be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations will be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment.


Study Number________________________________________________________________________

The same method of assessment and the same technique will be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment.

Please provide each measurement method and note specific timeframe(s) when each will be done (e.g., every 6 weeks, every 2 cycles, etc.). Examples include:

Conventional CT and MRI. These techniques will be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT will be performed using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis.

Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). List specific techniques to be used, and related time frames.

The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.

6.1.4 Response Criteria

6.1.4.1 Evaluation of Target LesionsComplete Response (CR): Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions.

Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.

Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

6.1.4.2 Evaluation of Non-Target LesionsComplete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. Specify tumor marker(s) to be used.

Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Specify tumor markers(s) to be used.

Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.


Study Number________________________________________________________________________

6.1.4.3 Evaluation of Best Overall ResponseThe best overall response (OR) is considered the best response recorded from the start of the treatment until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since the treatment started. The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

Table XXX: Overall Response Criteria

Target Lesions

Non-Target Lesions

New Lesions

Overall Response

Best Response for this Category Also Requires:

CR CR No CR At next scheduled time point

CR Non-CR/Non-PD No PR At next scheduled time point

PR Non-PD No PR

SD Non-PD No SDDocumented at least once >4 wks. from baseline, at

next scheduled visitPD Any Yes or No PD

No prior SD, PR or CRAny PD* Yes or No PDAny Any Yes PD

* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.

Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time will be reported as “symptomatic deterioration”. Every effort will be made to document the objective progression, even after discontinuation of treatment.

Note: If a subject responds to treatment and are able to have his or her disease resected, the patient’s response will be assessed prior to the surgery.

6.1.5 Duration of ResponseDuration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.

Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.

6.1.6 Progression-Free SurvivalProgression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression.


Study Number________________________________________________________________________

6.2 Antitumor Effect- Hematologic Tumors

Responses will document surrogate clinical activity and will also be reported consistent with iwCLL 2008 guidelines (see Appendix #/letter).

Baseline disease assessments will occur as indicated in Section 5.1. Final Response assessment will be assessed per iwCLL criteria, with clinical CRs confirmed by bone marrow biopsy and CT scan performed if previously abnormal. The primary efficacy point is defined as the patient response as assessed following 3 cycles of treatment.

6.2.1 Primary Efficacy/ Response assessment - clinical response following 3 cycles of treatment. If patient is clinically in CR (without or with cytopenias), peripheral blood will be assessed for clonal lymphocytes.

6.2.2 Final Response Assessment- Will occur two months following completion of treatment with (study agent). It is acknowledged that to meet iwCLL Guidelines for response in CLL, a response assessment must be performed 2 months from therapy to document responses including a bone marrow to confirm CR and a CT maybe indicated or recommended. Therefore, those patients that clinically appear to be in CR will have a bone marrow and possibly a CT scan to confirm complete responses at least 3 months after all treatment.

6.3 Safety/tolerability

Analyses will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE version 4.0 for reporting of non-hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic adverse events (Appendix #/letter).

7.0 ADVERSE EVENTS

7.1 Experimental TherapyFor the most recent safety update, please refer to the current Investigator’s Brochure or Study Agent Prescribing Information.

7.1.1 Contraindications

7.1.2 Special Warnings and Precautions for Use

7.1.3 Interaction with other medications

7.1.4 Adverse Reactions

7.2 Adverse Event Monitoring

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. Additionally, certain adverse events must be reported in an expedited manner to allow for optimal monitoring of patient safety and care.

All patients experiencing an adverse event, regardless of its relationship to study drug, will be monitored until:


http://ctep.cancer.gov/

Study Number________________________________________________________________________

the adverse event resolves or the symptoms or signs that constitute the adverse event return to baseline;

any abnormal laboratory values have returned to baseline; there is a satisfactory explanation other than the study drug for the changes

observed; or death.

7.3 Definitions

7.3.1 Definition of Adverse EventAn adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an experimental intervention, whether or not related to the intervention.

7.3.2 Severity of Adverse EventsNote, some hematology studies may choose to grade toxicity using alternatives to the CTCAE v4.0 (e.g., iwCLL criteria). When an alternative is used, please modify this section as needed. If using the CTCAE state:

All non-hematologic adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html

If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily activities.Moderate (grade 2): the event causes discomfort that affects normal daily activities.Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status.Life-threatening (grade 4): the patient was at risk of death at the time of the event.Fatal (grade 5): the event caused death.

7.3.3 Serious Adverse EventsA “serious” adverse event is defined in regulatory terminology as any untoward medical occurrence that:

7.3.3.1 Results in death.If death results from (progression of) the disease, the disease should be reported as event (SAE) itself.

7.3.3.2 Is life-threatening.(The patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe).


http://ctep.cancer.gov/reporting/ctc.html

Study Number________________________________________________________________________

7.3.3.3 Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 hours.

7.3.3.4 Results in persistent or significant disability or incapacity.

7.3.3.5 Is a congenital anomaly/birth defect

7.3.3.6 Is an important medical event

Any event that does not meet the above criteria, but that in the judgment of the investigator jeopardizes the patient, may be considered for reporting as a serious adverse event. The event may require medical or surgical intervention to prevent one of the outcomes listed in the definition of “Serious Adverse Event“. For example: allergic bronchospasm requiring intensive treatment in an emergency room or at home; convulsions that may not result in hospitalization; development of drug abuse or drug dependency.

7.4 Steps to Determine If an Adverse Event Requires Expedited ReportingStep 1: Identify the type of adverse event using the NCI Common Terminology Criteria

for Adverse Events (CTCAE v4).

Step 2: Grade the adverse event using the NCI CTCAE v4.

Step 3: Determine whether the adverse event is related to the protocol therapy Attribution categories are as follows:- Definite – The AE is clearly related to the study treatment.- Probable – The AE is likely related to the study treatment.- Possible – The AE may be related to the study treatment.- Unrelated – The AE is clearly NOT related to the study treatment.

Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any event that occurs more than 30 days after the last dose of treatment and is attributed (possibly, probably, or definitely) to the agent(s) must also be reported accordingly.

Step 4: Determine the prior experience of the adverse event. Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either the type of event or the severity of the event is not listed in:

the current known adverse events listed in the Agent Information Section of this protocol;

the drug package insert; the current Investigator’s Brochure

7.5 Reporting Requirements for Adverse Events

Definitions (Ref: HRRC Guidelines 2010)

Harm: The infliction of anything detrimental to one’s privacy, rights, comfort, health, property or success resulting in pain, suffering, or loss. Harms may include death and injury or damage to one's psychological, social, economic or legal status. Harms may affect individuals as well as specific population subgroups.


Study Number________________________________________________________________________

Unanticipated: An event is “unanticipated” when it was unforeseeable at the time of its occurrence. The word unanticipated, is not a synonym for unexpected. A research protocol can monitor for an unexpected event, but cannot monitor for an unanticipated event. All unanticipated events are unexpected, but not vice versa.

Unanticipated Problem Involving Risks to Participants or Others: Any event that (1) is unanticipated, (2) caused harm or placed a person at increased risk of harm, and (3) is related to the research procedures.

Reporting a Reportable Event - Events that require reporting to the HRRC should be reported using the Event Form. This form must be completely filled out and signed/dated by the principal investigator. A co-investigator may sign in the PI's absence so as not to delay reporting. Supporting documentation should be attached to the event form. A copy of the applicable pages(s) of the current informed consent document should also accompany the event packet.

Reporting a Non-Reportable Event - Investigators must assess all events that occur during the course of the research to determine if they meet reporting criteria (1.Unanticipated, 2. Caused harm or placed a person at increased risk of harm, AND 3. Was more likely than not related to the research). If the three criteria are not met, Investigators should keep a copy of the completed Tracking Log for Non Reportable Events (attached to supporting documentation in their regulatory binder as part of Good Clinical Practice (GCP). This will provide documentation that all events were assessed and did not meet reporting criteria. If the three criteria are met, then an Event Form should be completed and submitted to the HRRC.

The HRRC no longer accepts IND safety reports that do not meet all three reportingCriteria.

7.5.1 Reportable Events: Expedited Reporting

The Investigator(s) must ensure that during and following a participant’s involvement in a clinical trial that adequate medical care is provided to a participant for any adverse events, including clinically significant laboratory values, related to the clinical trial.

An Adverse Event (AE) is defined locally as “…any increase in risk of harm or actual harm experienced by a participant regardless of whether the event was internal to the treating institution or external - regardless of whether the event meets the FDA definition of "serious adverse event" - which in the opinion of the principal investigator are both unexpected and related to the research.

Adverse events not meeting these criteria do not need to be reported. An Adverse Event is "unexpected" when its specificity and severity are not accurately reflected in the informed consent document. An Adverse Event is "related to the research" if in the opinion of the principal investigator, it was more likely than not to be caused by the research (or if it is more likely than not that the event affects the rights and welfare of current participants).

Note: an AE can include a breach of confidentiality (including HIPAA violations and omissions).

Examples: the following events meet the definition of a reportable event:

1. Any serious event (injuries, side effects, deaths or other problems), which in the opinion of the Principal Investigator was unanticipated, involved risk to subjects or others, and was possibly, probably or definitely related to the


Study Number________________________________________________________________________

research procedures. Any serious accidental or unintentional change to the IRB-approved protocol practices that increases the level of risk.

2. Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research subject.

3. Any new information (e.g., publication, safety monitoring report, updated sponsor safety report), interim result or other finding that indicates an unexpected increase in the risk/benefit ratio for the research.

4. Any breach in confidentiality that may involve risk to the subject or others.

5. Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by the Principal Investigator.

Note: Failure to report adverse events in a timely manner is considered noncompliance.

Sponsors frequently agree to pay for injuries or adverse events arising out of research studies. Investigators should be familiar with the specific terms of any related sponsor agreement(s) so that they can discuss this with the prospective subject, and include the proper information in the consent form as appropriate.

The Principal Investigator must be notified within 24 hours of learning of any serious adverse events, regardless of attribution, occurring during the study or within 30 days following the last administration of the study drug.

HRRC Studies: Investigators must report events to the HRRC as soon as possible but no later than 5 days from the event date or “site awareness date.”

Western IRB Studies: All reports to the IRB of unanticipated problems should explain clearly why the event is "unanticipated" and clearly explain why the event represents a “problem involving risks to human subjects or others.” WIRB expects reports to the IRB of unanticipated problems to include a corrective action plan to address the issue, or written justification for why none is provided.

The IRB of record (HRRC or WIRB) must be notified within 10 business days of “any unanticipated problems involving risk to subjects or others.”

For IND/IDE trials: The FDA must be notified within 7 business days of any unexpected fatal or life-threatening adverse event with possible relationship to study drug, and 15 business days of any event that is considered: 1) serious, 2) unexpected, and 3) at least possibly related to study participation.

7.5.2 Routine Reporting All other adverse events- such as those that are expected, or are unlikely or

definitely not related to the study participation will be reported at least annually as part of regular Data Safety and Monitoring Committee (DSMC) and IRB review.


Study Number________________________________________________________________________

7.6 Unblinding ProceduresWhile the safety of the subject always comes first, it is still important to seriously consider whether unblinding the study therapy is necessary to ensure a subject’s safety.

This section should clearly describe the procedures for unblinding study therapy for a subject, including documentation of this in the subject’s source document. For investigators, other than the sponsor-investigator, state that the investigator must inform the sponsor of all subjects whose treatment was unblinded – and describe the timelines for such reporting. In most cases, the unblinding will be part of managing an SAE, and will be reported with the SAE, however, in cases where unblinding was not associated with an SAE, such actions should be reported in a timely manner. While there is no regulation governing this timeline, it is suggested to use the same timeline requirements for investigator reporting of SAEs, (e.g., notification of sponsor within 24 hours by phone or fax, followed by a written narrative of the event within 48 hours.)

7.7 Stopping Rules In studies with a primary safety endpoint or studies with high risk to study subjects, rules should be developed that clarify the circumstances and procedures for interrupting or stopping the study

NOTE: The UNM Cancer Center Data and Safety Monitoring Committee (DSMC) is set up to review this interventional study. The stopping rules should be incorporated into their safety analysis plan as well.

If your study will have stopping rules for inadequate efficacy (FUTILITY), please describe them here.

8.0 DRUG OR OTHER AGENT INFORMATION

8.1 Agent XXXFor each drug/agent provide the following:

Chemical/common name names for the drug(s) and/or agent(s):

Commercial name(s) for the drug(s) and/or agent(s)

Classification – type(s) of agent:

Mode(s) of action:

Storage and stability for each drug and/or agent:

Protocol dosage(s): (if a drug is given at different doses at different points in the treatment cycle, all doses should be clearly indicated.)

Preparation instructions for each drug/agent:

Route(s) of administration for this study:

Known Incompatibilities:

Availability of each study drug/agent: (e.g., “commercially available”, “provided by sponsor”; specify if provided free of charge, as this has implications for the Informed Consent Form.)


Study Number________________________________________________________________________

Side effects of each study drug/agent: A brief summary of the adverse events most likely to occur in this study and associated with this agent should be inserted here.

ATTACH the study agent package insert for each drug and/or agent to be used, if available with associated comprehensive listings of known toxicities.

Nursing implications – STUDY COMPLEXITY: please comment briefly:

8.1.1 Return and Retention of Study DrugPlease include sponsor/collaborator contact information including current address(es) and for all related agent/drug return and destruction policy(ies). If remaining drug is to be destroyed, please reference the drug destruction policy according to the current UNMCC and/or NMCC Alliance Standard Operating Procedures (SOP) or other appropriate instructions.

8.1.2 Please include, if applicable, plans for documentation of subjects’ compliance with the study agent, if applicable e.g., questionnaire, patient diary, pill diary (Required for all oral or self-administered investigational agents), etc. Other sections may be required/requested by sponsor.

Attach study-specific Case Report Forms (CRFs) if applicable.

9.0 CORRELATIVES/SPECIAL STUDIES (As Applicable)

The goal of the planned laboratory correlative studies is to: _____________

Indicate whether submission of samples for correlative studies is mandatory (eligibility requirement) or optional for participation in this study. As needed, reference any separate Informed Consent Form(s) and specific eligibility requirements.

9.1 Sample Collection GuidelinesPlease list in detail:

a) specific type(s) and amount(s) of samples to be collected; b) method(s), time frame(s) and special materials for collection/preservation; c) sample preparation and handling procedures (types and numbers of tubes;

centrifuged at ____ for ___ minutes; frozen (e.g., snap frozen; transported on wet/dry ice, fixed in ___);

d) specific sample storage conditions, including temperature(s) etc. as applicable. You may consider inserting a table to describe collection guidelines here.

Example: “Samples will be collected at the following time points (+/- window, as applicable):

Within 28 (+/- 2) days prior to study treatment Within 2, 4, 8, 16, and 32 hours post-treatment

Include a statement such as: “All samples will be labeled with the subject’s de-identified study number (unique study ID number) and collection date.” Specimens will be stored as outlined (if applicable) and delivered for analysis to:

<Insert Location/Address>


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Include detailed instructions for preparation and shipment (e.g. send by overnight mail or batched, etc).

Please include any restrictions on specimen receiving times (e.g., after hours, weekends, holidays) if applicable.

9.2 Assay Methodology (with references)

9.3 Specimen BankingSAMPLE LANGUAGE:<use any as applicable>

a. Patient samples will be collected for this study from the following clinical practice(s) {1,2,3… } and will be retained at (where). Specimens will be stored indefinitely or until (specify time frame). If future use is denied or withdrawn by the patient, best efforts will be made to stop all additional studies and to destroy the specimens.

b. Name/Department will be responsible for reviewing and approving requests for clinical specimen from potential research collaborators outside of the UNM Cancer Center (or other institution).

c. Collaborators may be required to complete an Institutional Agreement that states specimens will only be released for use in disclosed research, with or without return of residual materials. Any data obtained from the use of clinical specimen will be the property of {INSTITUTION} for publication and any licensing agreement will be strictly adhered to.

d. Individual specimens, DNA/RNA isolates, and their derivatives may have significant therapeutic or commercial value. The Informed Consent Form contains provides information and informs the subject that there is the potential for financial gain by {INSTITUTION}, the investigator or a collaborating researcher or entity.

The following information obtained from the subject's medical record may be provided to research collaborators when specimens are made available:

Diagnosis Collection time in relation to study treatment Clinical outcome – if available Demographic data

10.0 STATISTICAL CONSIDERATIONSPlease describe the statistical aspects of the protocol in fine detail, including references.

This section should be written in coordination with the study statistician. It should precisely describe for each objective the units of measure to be used, the objective-specific target numbers of (individuals, specimens, etc.) and how each data set will be analyzed for potential statistical significance. Include each type of statistical measure (confidence intervals; Mean +/- Standard Deviation, etc.) those results will be calculated.

10.1 Study Design/Study EndpointsPlease specify the study design. State clearly key design aspects, such as: retrospective or prospective, blinded, randomized, single or multi-centered. Define each study endpoint separately (For example, do not combine endpoints in a single objective, such as “efficacy and toxicity of agent xxx.”


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If there are stopping rules for either safety or efficacy, describe the reasoning behind them, and how they might cause a suspension of study enrollment until a safety review has been convened. Examples of findings that might trigger a safety review are the number of SAEs overall, the number of occurrences of a particular type of SAE, severe AEs/reactions, or increased frequency of events.

10.2 Sample Size and AccrualJustification for the number of patients to be used in the study must be given. Please state precisely what the statistical power and sample size considerations will be employed for the proposed study, and which specific objective they address. (Separate the SINGLE primary objective from each SECONDARY objective.) The total sample size, the total minimum accrual/completions of study procedures, the expected accrual rate, and all relevant assumptions should be stated explicitly.

Please describe how these numbers were calculated, including the software used. (Note: A reviewer should be able to duplicate the calculations given the information provided.)

10.3 Data Analyses PlansPlease describe in detail how EACH SEPARATE OBJECTIVE will be assessed by a particular data analysis plan. Please provide specific details of each data analysis plan (for each objective), stating which units of measure and statistical methods will be used, and under which assumptions.

It is very important that each individual objective, and each associated study endpoint should have a plan clearly associated with it. Further details concerning safety and/or pharmacokinetics, may be given here as well.

11.0 STUDY MANAGEMENT

11.1 Conflict of Interest

Any investigator who has a potential conflict of interest with this study (patent ownership, royalties, or financial gain greater than the minimum allowable by local and other guidelines) must have the conflict reviewed by the UNM Conflict of Interest Committee (COIC) prior to Institutional Review Board review. All investigators will follow the University of New Mexico Health Sciences Center conflict of interest policy.

11.2 Institutional Review Board (IRB) Approval and Consent Only accredited Institutional Review Board(s) (IRBs) will have oversight for this clinical research study. Reviews and outcomes will function in accordance with Federally mandated regulations. The IRB will review and approve the study protocol including consent practices and data security, the Informed Consent Form(s) and other study-specific documents as required.

In obtaining and documenting informed consent, the investigator will comply with the applicable regulatory requirement(s), and will adhere to Good Clinical Practice (GCP) and to ethical principles that have their origin in the Declaration of Helsinki(1).

Before recruitment and enrollment into this study, each patient will be given a full explanation of the study and will be provided ample opportunity to review the Informed Consent Form(s). Each consent form must include all the relevant elements currently required by the FDA Regulations and local or state regulations. Once this essential information has been provided to the patient and the investigator is assured that the


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patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing an IRB-approved consent form.

Prior to a patient’s participation in the trial, the written informed consent form should be signed and personally dated by the patient and by the person who conducted the informed consent discussion.

11.3 Required DocumentationBefore the study can be initiated at any site, the following documentation must be provided to the Clinical Trials Office: A copy of the official IRB approval letter for the protocol and informed consent(s) IRB-approved consent form(s) and other documents as applicable Curriculum Vita and medical licensure for the principal investigator and each

associated (co-) investigators who will be involved in the study Form FDA 1572 appropriately filled out and signed with appropriate documentation) Form FDA 1571 (Investigational New Drug) assignment or FDA letter of exemption CAP and CLIA Laboratory certification numbers and institution lab normal values Dually executed clinical research contract or other agreements, as applicable PowerPoint presentation (Study Team training requirement for interventional studies) Documentation of study team training

11.4 Registration ProceduresFor UNMCC Clinical Trials Office/ NMCC Alliance managed Studies, please use the following boilerplate language:

Prior to registration, eligibility criteria must be confirmed with the UNMCC Clinical Trials Office Quality Assurance Department. Each signed consent form(s) must be submitted for each patient by FAX (505) 272-7799, ATTN: Quality Assurance

If the patient meets the eligibility criteria he/she will be assigned a patient study number by calling the Clinical Trials Office Clinical Research Supervisor at 505-925-0389.

Data for patients enrolled on interventional trials must be entered per current practices into the Velos eResearch electronic clinical trials management system.

The study Principal Investigator must identify which electronic Case Report Form(s) will be required for data collection pertinent to the study. As needed, study-specific Case Report Forms will be developed, reviewed and approved by the PI prior to first patient enrollment.

Please complete the attached Velos eCRF checklist (see Appendix B) to this protocol, including any study-specific CRFs to be used.

11.5 Adherence to the ProtocolExcept for an emergency situation in which proper care for the protection, safety, and well-being of the study patient requires alternative treatment, the study shall be conducted exactly as described in the approved protocol.

11.5.1 Emergency ModificationsInvestigators may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB approval.


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For any such emergency modification implemented, a IRB modification form must be completed within five (5) business days of making the change.

11.5.2 Other Protocol Deviations/ViolationsAll other planned deviations from the protocol must have prior approval by the Principal Investigator and the IRB of record. According to the IRB, a protocol deviation is any unplanned variance from an IRB approved protocol that: Is generally noted or recognized after it occurs Has no substantive effect on the risks to research participants Has no substantive effect on the scientific integrity of the research plan or the

value of the data collected Did not result from willful or knowing misconduct on the part of the

investigator(s).

An unplanned protocol variance is considered a violation if the variance: Has harmed or increased the risk of harm to one or more research

participants. Has damaged the scientific integrity of the data collected for the study. Results from willful or knowing misconduct on the part of the investigator(s). Demonstrates serious or continuing noncompliance with federal regulations,

State laws, or University policies.

If a deviation or violation occurs without prior approval from the Principal Investigator, please follow the guidelines below:

If {non-Research Office} managed study, please maintain the following language in your protocol:

Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring committee in accordance with their policies. Deviations should be summarized and reported to the IRB at the time of continuing review.

Protocol Violations: Study personnel should report violations within one (1) week of the investigator becoming aware of the event using the same IRB online mechanism used to report Unanticipated Problems.

11.6 Amendments to the ProtocolShould amendments to the protocol be required, the amendments will be originated and documented by the Principal Investigator in conjunction with the Clinical Trials Office CRA and Nurse Manager. Note: when an amendment to the protocol substantially alters the study design or the potential risk to the patient (considered a “Scientific Change” per the UNMCC/CTO Data Safety and Monitoring Plan), a revised consent form may be required. Additionally, the study PI must determine whether ongoing study accrual should be temporarily stopped, pending approval of the amended protocol.

The amended protocol, with new version number and date, and as required the amended consent form, must be approved by the IRB of record for approval prior to implementation.

11.7 Record RetentionStudy documentation includes all Case Report Forms, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, reports and regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms, FDA forms 1571, 1572).


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Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study.

Government agency regulations and directives require that the study investigator must retain all study documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking regulatory approval and marketing, these documents shall be retained for at least two years after the last approval of marketing application in an International Conference on Harmonization (ICH) region. In all other cases, study documents should be kept on file until three years after the completion and final study report of this investigational study.

11.8 Obligations of InvestigatorsThe Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of all study patients. The Principal Investigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study completion.

The Principal Investigator at each institution or site will be responsible for assuring that all required data will be collected and entered onto the Case Report Forms. Periodically, monitoring will be conducted according to the most current version of the UNMCC CTO Data Safety and Monitoring Plan, and the Principal Investigator will provide access to his/her original records to permit verification of proper entry of data. At the completion of the study, all printed case report forms will be reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of the data.

11.9 Data Management and Monitoring/Auditing (Please see Appendix A)The University of New Mexico Cancer Center (UNM CC) places a high priority on ensuring the safety of patients participating in clinical trials. All clinical trials require monitoring commensurate with the degree of risk involved in participation of studies. Standard Operating Procedures (SOP’s) detail functions and processes found in this plan. SOP’s are available at h ttp://hsc.unm.edu/UNM CC/intranet/ctoforms.asp .

Data and safety monitoring activities for each study continue until all patients have completed their treatment and all patients are beyond the time point at which study-related adverse events would likely be encountered. The UNM CC has implemented a process for routine real time data monitoring and safety review of Investigator Initiated trials which takes into account the Essential Elements of the National Cancer Institute (NCI) guidelines, the FDA monitoring regulations, Good Clinical Practice Guidelines and other DSM plans and programs approved by the NCI.

In addition to complying with NIH/NCI guidelines, the UNM CC DSMP complies with, the University of New Mexico Health Sciences Center Human Research Protections Office (HRPO) guidelines for safety and data monitoring which can be found at: http://hsc.unm.edu/som/research/hrrc/PoliciesGuidelines.shtml).

The DSMP is distinct from, and complements, the activities of the Protocol Monitoring & Review Committee (PRMC) and the Clinical Protocol Data Management & Informatics (CPDMI) functions of UNM CC.


http://hsc.unm.edu/som/research/hrrc/PoliciesGuidelines.shtml

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12.0 REFERENCESPlease list all relevant references here, and re-number the following 4 standard references.

1. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects

2. HRRC Guidelines, v. 2010 or most current3. WIRB Reporting System for Unanticipated Problems that Are Adverse Events, v. 01/2009R2 or

most current4. WIRB Reporting System for Unanticipated Problems that are Not Adverse Events, v.08/2010 or

most current.

13.0 APPENDICES Please list all relevant appendices in alphabetical order, e.g., Appendix A, Appendix B, etc.

Appendix A: University of New Mexico Cancer Center and New Mexico Cancer Care Alliance Data and Safety Monitoring Plan 2010

Appendix B: Electronic Case Report Forms Required for this Study

(Please include a Pill Diary for each self-administered investigational agent)

Appendix C: (as applicable) Package Insert(s)

14.0 ADDITIONAL INFORMATION FOR HRRC REVIEW

As in Part 1 above, the sections/language in BLUE are instructions and should be modified according to your specific study design. When the document is complete, all remaining sections in BLUE should be modified to the specifications of your study and updated to BLACK type.

Depending on the nature of what you are doing, some sections may not be applicable to your research. If so, mark as “NA” and briefly explain why it doesn’t apply.

If this research is HHS-supported (e.g., NIH funded) and UNM HSC is the prime awardee or serving as the IRB of record for the prime awardee, include a copy of the grant application and sample consent (if applicable).

All checklists referenced in this protocol can be found in Click under the “IRB” tab, in the “IRB Library”.

When you write a protocol, keep an electronic copy. You will need to modify this copy when making changes.

14.1 Regulatory Framework:

Please indicate all that apply:


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DOD (Department of Defense)

DOE (Department of Energy)

DOJ (Department of Justice)

ED (Department of Education)

EPA (Environmental Protection Agency)

FDA (Food and Drug Administration)

HHS (Department of Health and Human Services)

VA

Other:

Is this a clinical trial under ICH-GCP E6? Yes No If yes, please confirm that the research team is familiar with and agrees to

comply with the investigator requirements cited in ICH-GCP E6.

Yes No

ICH-GCP E6 can be accessed by copying and pasting this URL into your browser: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf

14.2 Study Timelines Describe the duration of an individual subject’s participation in the research Describe the duration anticipated to enroll all subjects Describe the expected duration for the investigators to complete the study (complete

analysis)

14.3 Research Setting Describe the sites or locations where your research team will conduct the research.

Identify where your research team will identify and recruit potential subjects.

Identify where research procedures will be performed including any laboratory analytics

Describe the composition and involvement of any community advisory board

For research conducted outside of UNM HSC and its affiliates describe:

o Site-specific regulations or customs affecting the researcho Local scientific and ethical review structure/requirements (Note: include any

approvals (IRB, facility, or other) with your submission)

14.4 Resources AvailableThe PI and study staff have all completed the mandatory training per New Mexico Cancer Care Alliance participation requirements. All staff completes the human research protections training bi-annually.

The UNM Cancer Center’s highly trained oncology physicians carefully coordinate patient care through multidisciplinary teams. Each multidisciplinary team includes oncology, surgical, and radiation physicians, pathologists, and radiologists with expertise in specific


http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf

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cancer types. Each team also includes mid-level and ancillary providers, such as nurse practitioners and physician assistants. In addition, a nutritionist, genetic counselor, and psychologist support each team as patient needs require.

14.5 Prior Approvals

This study has been reviewed by the Protocol Review and Monitoring Committee of the New Mexico Cancer Care Alliance.

No prior IRB approvals have been obtained for this study.

14.6 Multi-site ResearchIf this is a multi-site study where the UNM HSC PI is the lead investigator, or UNM HSC is the coordinating site, describe the processes to ensure communication among sites, such as:

All sites have the most current version of the protocol, consent document, and HIPAA authorization.

All required approvals have been obtained at each site (including approval by the site’s IRB of record).

All modifications have been communicated to sites, and approved (including approval by the site’s IRB of record) before the modification is implemented.

All engaged participating sites will safeguard data as required by local information security policies.

All local site investigators will conduct the study appropriately. All non-compliance with the study protocol or applicable requirements will reported in

accordance with local policy.

Describe the method for communicating to engaged participating sites:

Adverse events Problems Interim results Data and safety monitoring reports The closure of a study

If the UNM HSC investigator is serving as the “sponsor-investigator” of a FDA-regulated trial, describe how sponsor responsibilities will be fulfilled, including, but not limited to:

Trial Monitoring Investigational Product Accountability Safety and other interim reporting to investigators and FDA Unanticipated Problem reporting to investigators, IRBs, and FDA

14.7 Study ProceduresFor research procedures and interventions being performed describe:

Each drug, biologic, device, or other such product used in the research, the purpose, and the regulatory status (e.g., investigational, marketed – on label, marketed – off label, etc.)

Each survey, questionnaire, interview, focus group, etc., that subjects will be asked to complete or participate in for the research and the purpose of it.

Indicate whether subjects would already be expected to undergo any of the procedures for clinical, diagnostic, or other non-research purposes


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Include all referenced study instruments, such as questionnaires, scripts, diaries, and data collection forms with your submission as separate attachments.

For HUDs, provide a description of the device, a summary of how you propose to use the device, including any screening procedures, the HUD procedure, and any patient follow-up visits, tests, or procedures. Note whether the HUD is being used for clinical purposes only or if you are proposing to study the safety or effectiveness of the device.

14.8 Data Management/ConfidentialityThe UNMCC Clinical Research Office (CRO) maintains the electronic clinical trials management system, Velos eResearch. Investigator initiated trials falling under the Cancer Center’s Data and Safety Monitoring Plan (DSMP) guidelines are subject to ongoing, electronic monitoring. To facilitate this and other processes, electronic Case Report Forms (eCRFs) are used in the Velos system. The study Principal Investigator, statistician, and lead CRO staff will meet in advance to ensure proper application of standard eCRFs (already in Velos) and/or development of study-specific eCRFs. Source data based on laboratory and imaging tests which are needed to address study objectives will be transferred into the Velos database by CRO staff. Patient study, or “shadow” charts will be maintained by CRO staff for the duration of this study as well.

14.9 Data and Specimen BankingIf data or specimens will be banked or archived locally for future use, provide the name and IRB number of the repository that they will be deposited into.

Describe exactly what data or specimens will be banked and for what purposes, and whether the data or specimens will include identifiers, be coded, or be fully stripped of all identifiers with no code or key that would allow relinking.

Be certain to describe the banking in the primary consent. A separate consent and authorization, if applicable, will be necessary for the banking activity itself and is typically provided by the repository.

If you need to establish a repository for the purposes of banking or archiving data or specimens, a separate submission for the repository is needed as this is considered to be a distinct research activity under the regulations.

If this is a multi-center study, and/or if data or specimens will be banked or archived elsewhere, identify who the holder of the data or specimens will be, exactly what data or specimens will be banked and for what purposes, and whether the data or specimens will include identifiers, be coded, or be fully stripped of identifiers with no code or key that would allow relinking.

A Materials Transfer or other agreement may be necessary, please consult with the HSC Sponsored Projects Office at 505-272-6264 or by email at [email protected]. Material Transfer Agreement procedures may be found at http://hsc.unm.edu/financialservices/preaward/ancillary-agreements/material-transfer-agreements/procedures.html. Be certain to describe the banking in the consent and authorization, using opt-in procedures, and the procedures for subjects to request withdrawal of their data or specimens and any limitations on their ability to do so.

14.10 Risks to Subjects List the reasonably foreseeable risks, discomforts, hazards, or inconveniences to the

subjects related the subjects’ participation in the research. Describe the probability, magnitude, duration, and reversibility of the risks. Consider physical, psychological,


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social, legal, and economic risks. Note that almost all research includes confidentiality risks.

If applicable, indicate which procedures may have risks to the subjects that are currently unforeseeable.

If applicable, indicate which procedures may have risks to an embryo or fetus should the subject be or become pregnant. If pregnancy testing or birth control provisions are required, describe these.

If applicable, describe risks to others who are not subjects.

Describe the steps being taken to minimize the probability or magnitude of risks.

Note: All risks described here should also be described in the consent document.

14.11 Prior Approvals

There may or may not be direct benefit to the patient from participating in this study. However, it is hoped that the information gained from the study will help in the treatment of future patients with _____________________________

14.12 Recruitment Methods Describe when, where, and how potential subjects will be recruited.

Describe the methods that will be used to identify potential subjects (e.g., chart review, referral, etc.).

Describe materials that will be used to recruit subjects (e.g., emails, scripts, advertisements, brochures, flyers, etc.). Attach draft copies of the documents or audio or video recordings with the application. Once the draft has been approved, the final copy of the printed material, audio or video recording must be submitted for review and approval prior to implementation. Please see Worksheet HRP-315 for information on advertisement standards.

14.13 Provisions to Protect the Privacy Interests of SubjectsEfforts will be made to keep patients’ personal information confidential, and UNM Cancer Center’s procedures include removing patients’ names and other identifying information from data collected during the study in order to protect their privacy. However, we cannot guarantee total confidentiality.

Paper based records will be kept in a secure location and only be accessible to personnel involved in the study. Computer-based files will be available to study personnel through the use of access privileges and passwords. Prior to obtaining access to identifiable information, study personnel will be required to sign statements agreeing to protect the security and confidentiality of identifiable information.

Whenever feasible, identifiers will be removed from study-related information.

14.14 Economic Burden to SubjectsDescribe any costs that subjects may be responsible for because of participation in the research. Clearly stipulate what procedures are standard of care and what procedures


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are research-related in the table below. Please place an X in the box for the responsible party for each procedure involved.

List any costs to participants (or their 3rd party payer); include any charges for study procedures, visits, or drug/devices.

Research Procedures Number of Samples/Procedures

Responsible Party

Study 3rd Party Payer or

Participant

Standard of Care Procedures Number of Samples/Procedures

Responsible Party

Study 3rd Party Payer or

Participant

List any other costs to participants not already described above.

Indicate whether subjects will be charged for investigational drugs, devices, procedures

Explain who will be responsible for paying for treatment of adverse events

Ensure that the cost section of the consent form reflects the cost that are covered by the sponsor and the costs for which the subjects (or 3rd party payers) are responsible.


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14.15 CompensationPatients will not be paid for taking part in this study

OR

Describe any plans for compensation or reimbursement for subjects (amounts, methods (e.g., cash card), and payment schedule).

Describe why the proposed amount is reasonable and appropriate for the subjects’ time and inconvenience. Credit for payment should be prorated and not be contingent upon the participant completing the entire study. Any amount paid as bonus for completion of the entire study should not be so great that it could unduly induce subjects to remain in the study when they otherwise would have withdrawn.

Note: Consult with your department official for reporting requirements associated with cash or merchandise cards distributed to research subjects.

14.16 Compensation for Research-Related InjuryDue to the low risk of this study, research related injury is not expected.

OR

The patient will get medical treatment if they are injured as a result of taking part in this study. However, the patient and/or their health plan will be charged for this treatment. The study will not pay for medical treatment.

14.17 Consent ProcessIn a location that provides privacy, study personnel review all of the elements of the study, provide an overview of the study, explain its purpose, procedures, risks and benefits, drug and comparative agent (if applicable), alternatives, research-related procedures, etc. After having described the study to the patient, the attending physician or the research nurse will provide the subject with a paper of copy of the consent form. The subject is told to write questions he/she could have about the study. At the next visit, the study personnel (Principal Investigator and/or Research nurse) then go over the consent with the subject and answer any questions the subject may have.

When all questions are answered to the subject’s satisfaction and he/she agrees to participate in the study, the subject places their initials or marks on all pages of the consent except the last page, which is the signature page. The subject signs the signature page with their full signature and date.

During the discussion with the subject at the time they are considering participation in this study, they will be asked to repeat the important information and key points in their own words about the research project to assure that they understand the information. Subjects will be reminded during informed consent and throughout the study that their participation is strictly voluntary and that they may withdraw for any reason and at any time, without penalty. No claims will be made to the subject as to the efficacy of the experimental treatment. Subjects will also be informed that there are alternatives to their participation in the study.

The subject is allowed adequate time (usually at least 24 hours) to review the consent in order to make a decision as to whether to participate, preferably taking the consent form home to discuss it with family practitioner, family members, and/or friends.


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Subjects not fluent in English

A Spanish Short Form will be used to consent Spanish speaking patients. A Certified translator will review the Main Consent Form with the patient.

Cognitively Impaired Adults/Adults Unable to Consent/Use of a Legally Authorized Representative

N/A – Cognitively impaired adults will not be enrolled.

Subjects who are not yet adults (infants, children, teenagers)

N/A- Subjects who are not yet adults will not be enrolled

Waiver or Alteration of Consent Process (consent will not be obtained, required element of consent will not be included, or one or more required elements of consent will be altered)

N/A- Consent will be obtained for this trial

OR

Complete the applicable checklists in the Checklists section of this Protocol Template if you are requesting a waiver or alteration of consent for this research

Consent can be waived for all of some subjects (e.g. the research includes a retrospective cohort)

Consent can be waived in full or in part (e.g. partial waiver for recruitment purposes)

14.18 Documentation of Consent Describe if you plan to use a consent form to document consent. Use the UNM HSC

consent generator or one of the consent templates available on the HRPO website. Attach consent documents as fully editable Word documents (i.e., please don’t submit protected documents or pdfs). Please include page numbers in the footer (e.g. Page 1 of XX).

If the study is collecting and/or storing tissue samples, include a Tissue Banking Consent Form (and Authorization if the specimens will be accompanied by PHI).

Describe if you plan to obtain consent but will be using a script, information sheet, or other mechanism. If you will obtain consent verbally, attach a consent script and information sheet, if you will be providing one. If you will be obtaining consent via an on-line survey, please use the survey cover letter consent template on the HRPO website and include your email script with your submission.

If you intend to obtain consent verbally but will not be obtaining signatures from subjects on a consent form to document consent, a Waiver of Documentation of Consent will need


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to be requested. Please contact the UNM clinical trials office to obtain assistance with this process. Waivers of documentation of consent are commonly requested when using scripts, information sheets, or email or survey introductions to present the elements of consent instead of using a traditional consent form. If you will be excluding or modifying one or more of the required elements of consent you will also need to request an Alteration of Consent.

14.19 Study Test Results/Incidental FindingsIndividual Results: Indicate whether you intend to share study test or procedure results with study participants If so, describe which results will be shared, whom the results will be shared with (e.g., subjects, parents, primary care physicians), and how the findings will be communicated (e.g., in person consultation, posting in medical record, etc.). If the findings are the results of laboratory tests, indicate whether the tests will be processed in a CLIA-certified lab.

Incidental Findings: Based upon the nature of the research, and the tests that will be performed, indicate if you anticipate that the research may result in incidental findings (traditionally defined as results that arise that are outside the original purpose for which the test or procedure was conducted (for example, a potential tumor is identified but this is not the reason imaging was obtained). If so, please describe your plans for communication of such results to subjects and their health care providers, if appropriate. If there are limitations on the accepted validity of the results (e.g., test performed in non-CLIA lab, test available in the context of research only), please describe and provide a plan for confirmatory testing or justification for why it is not recommended, not necessary, or not possible. If you do not plan to provide results, provide justification.

Be certain to describe your plans for provision of study results and incidental findings in your consent documents.

For more information on incidental findings, please consult the President’s Bioethics Commission Report “Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts”: http://bioethics.gov/sites/default/files/FINALAnticipateCommunicate_PCSBI_0.pdf

For information specific to Whole Genome Sequencing, please consult the President’s Bioethics Commission Report “Privacy and Progress in Whole Genome Sequencing”: http://bioethics.gov/sites/default/files/PrivacyProgress508_1.pdf

14.20 Sharing Study Progress or Results with Subjects Describe whether you intend to provide subjects with a summary of the trial progress

while the study remains underway. If so, describe your plans and the mechanisms that you will use (e.g., newsletter, handouts, mailings, etc.). Please note that all written materials that will be provided to subjects need to be reviewed and approved by the IRB prior to use.

Describe whether you intend to provide subjects with a summary of the study results after the study is complete. If so, indicate if the information will include study arm assignment if the study involved blinding. Please describe your plans for dissemination of results and the mechanisms that you will use. Please note that IRB review of materials may be required, consult with the HRPO prior to distribution.


Study Number________________________________________________________________________

14.21 Inclusion of Vulnerable PopulationsN/A- vulnerable populations will not be included in this study

14.22 Community Based Participatory ResearchN/A- This study is not community based participatory research or field research

OR

Describe involvement of the community in the design and conduct of the research. If members of the community will fulfill key research responsibilities such as recruitment and consent, describe what research activities community members will be responsible for, how they will be trained, and the plan for quality oversight. When relevant, please include information regarding the approval of the research at collaborating sites (e.g., Albuquerque Public Schools).

Note: “Community-based Participatory Research” is a collaborative approach to research that equitably involves all partners in the research process and recognizes the unique strengths that each brings. Community-based Participatory Research begins with a research topic of importance to the community, has the aim of combining knowledge with action and achieving social change to improve health outcomes and eliminate health disparities.

14.23 Research Involving Native American Indian/Native PopulationsN/A- this is not research involving American Indian/Native populations

OR

Please provide detailed information of the local research context including how the research questions are sensitive to community attitudes and how the PI has ascertained that the proposed research is acceptable to the local population in terms of tribal regulations, applicable law and standards of professional conduct and practice. Attach any supporting documents from tribal officials or entities addressing the status or requirements for review of the research activity from tribal officials or tribal entities (for example, Indian Health Services, the Navajo Nation IRB).

14.24 Transnational ResearchN/A- this is not transnational research

OR

When conducting transnational research, you must ensure that subjects are provided equivalent and appropriate protections for human subjects located outside of the United States. Please refer to the following website for current OHRP interpretations of research standards, equivalent protections, and for a current compilation of international research standards and regulatory agencies. http://www.hhs.gov/ohrp/international/index.html

Location: Describe the research locale and how and why the setting was chosen. Describe significant cultural norms, local laws, and differences with U.S. culture with


Study Number________________________________________________________________________

respect to autonomy, perception of research, recruitment, consent, age of majority, parental permission, etc.

Study Personnel: Describe the qualifications of the researcher and research team to perform research in the community/culture where it will occur. Indicate the research team’s ability to speak, read, and write the language of the subjects. Describe the researcher’s knowledge of or expertise in local or state laws, culture, and community norms. Indicate if the researcher was invited into the community (provide documentation, if available). If not invited, then describe how the researcher will have culturally appropriate access to the community.

Consent: Describe the consenting procedure that you intend to use for the research and why it is appropriate for the community where the research will occur. Describe how you will ensure that potential subjects understand the research, and the voluntariness of their participation.

Community Consultation: Describe any plans for community consultation to assess receptiveness to the proposed research and to obtain feedback on how it should be conducted and any limitations or boundaries that should be respected. Describe plans for dissemination of results to subjects and to the community.

14.25 Drugs or Devices If the research involves drugs or devices, describe your plans to store, handle, and

administer those drugs or devices so that they will be used only on subjects and be used only by authorized investigators.

If the drug is investigational (has an IND), identify the holder of the IDE/Abbreviated IDE.

For research involving drugs, complete and attach a signed “Drug Attachment”, available in Click or the HRPO website

For research involving devices, complete the “Device Checklist” in the Checklist Section of this template.


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